Atopic dermatitis (AD) is an itchy, inflammatory skin disease. It is one of the most common causes of human and canine disability. The incidence of human atopic dermatitis is steadily increasing. The mainstay of therapy for milder human disease is topical treatment. Patients with more severe disease suffer chronic itching and rash and often require systemic immunosuppressive therapy. Systemic corticosteroids are effective but have unacceptable side effects. Other systemic immunosuppressive medications, including methotrexate, are being investigated, but an effective, safe treatment for these patients has yet to be defined. It is estimated that 10% of dogs suffer from AD. Treating dogs with AD once or twice daily with topical medications is difficult and effective therapies are not available. Furthermore, canine AD (CAD) is the best pre- clinical model for AD. This has motivated investigators to investigate oral systemic immunosuppressive treatment for dogs so that an effective treatment for dogs and humans can be developed. The long term goal of this project is to develop aminopterin (AMT), an anti-folate drug closely related to methotrexate (MTX), for a variety of anti-inflammatory conditions, including canine and human AD. The interest in AMT stems from discoveries that AMT causes less adverse reactions than MTX, while being significantly more potent. For inflammatory indications AMT can be administered at low doses once weekly. Together these data argue that AMT will provide a better treatment option than MTX, and that AMT will be an important new, safe, cost-effective treatment for moderate to severe AD and other inflammatory diseases. In pursuit of developing AMT for the treatment of AD and other inflammatory diseases, a small open- label pre-clinical trial investigating the treatment of CAD was performed. This trial demonstrated that AMT was safe and effective. These results provide the foundation for a double-blind, randomized, placebo-controlled, dose-ranging trial investigating the safety and efficacy of low dose oral aminopterin for the treatment of CAD. The specific aims of this proposal are to: (1): Assess the safety of oral AMT in the treatment of canine atopic dermatitis. (2): Establish the dose-response relationship of oral AMT in canine atopic dermatitis. (3): Determine if twice weekly or once weekly dosing is preferred. The efficacy will be evaluated with validated measures. Completion of this proposal will define a dose and schedule for AMT treatment of CAD. These results will provide important pre-clinical data for the filing of an IND for human atopic dermatitis. PUBLIC HEALTH RELEVANCE Atopic dermatitis is a leading cause of human disability and improved therapies are needed. Ten percent of dogs also suffer atopic dermatitis and lack adequate therapy. Demonstrating that aminopterin is a safe and effective treatment of dogs with atopic dermatitis would serve an unmet need of dogs, and will greatly advance the development of a new treatment for people with moderate to severe atopic dermatitis.